{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T22:06:08Z","timestamp":1785189968399,"version":"3.55.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tristetraprolin (TTP), an mRNA-binding protein, plays a significant role in regulating the expression of adenylate-uridylate\u2013rich elements containing mRNAs. Mice deficient of TTP (TTP\u2212\/\u2212) develop a systemic autoimmune inflammatory syndrome characterized by cachexia, conjunctivitis, and dermatitis. IL-12 plays a crucial role in immune defense against infectious and malignant diseases. In this study, we found increased production of IL-12 during endotoxic shock and enhanced Th1 cells in TTP knockout mice. The levels of IL-12 p70 and p40 protein as well as p40 and p35 mRNA were also increased in activated macrophages deficient of TTP. In line with these findings, overexpression of TTP suppressed IL-12 p35 and p40 expression at the mRNA and promoter level, whereas it surprisingly had little effects on their mRNA stability. Our data showed that the inhibitory effects of TTP on p35 gene transcription were completely rescued by overexpression of NF-\u043aB p65 and c-Rel but not by the p50 in activated macrophages. Our data further indicated that TTP acquired its inhibition on IL-12 expression through blocking nuclear translocation of NF-\u043aB p65 and c-Rel while enhancing p50 upon stimulation. In summary, our study reveals a novel pathway through which TTP suppresses IL-12 production in macrophages, resulting in suppression of Th1 cell differentiation. This study may provide us with therapeutic targets for treatment of inflammatory and autoimmune disorders.<\/jats:p>","DOI":"10.4049\/jimmunol.1300126","type":"journal-article","created":{"date-parts":[[2013,8,31]],"date-time":"2013-08-31T04:32:38Z","timestamp":1377923558000},"page":"3922-3930","source":"Crossref","is-referenced-by-count":28,"title":["Suppression of IL-12 Production by Tristetraprolin through Blocking NF-\u043aB Nuclear Translocation"],"prefix":"10.1093","volume":"191","author":[{"given":"Ling","family":"Gu","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Ning","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Qian","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"},{"name":"Department of Neurology, The First Affiliated Hospital, Chongqing Medical University , Chongqing 400016,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hou","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajaa","family":"Almourani","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingui","family":"Fu","sequence":"additional","affiliation":[{"name":"Shock and Trauma Research Center, Department of Basic Medical Science, School of Medicine, University of Missouri , Kansas City, MO 64108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry J","family":"Blackshear","sequence":"additional","affiliation":[{"name":"National Institute of Environmental Health Sciences , Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine , St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,10,1]]},"reference":[{"key":"2025032405421160800_r1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1084\/jem.170.3.827","article-title":"Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes","volume":"170","author":"Kobayashi","year":"1989","journal-title":"J. Exp. Med."},{"key":"2025032405421160800_r2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nri1001","article-title":"Interleukin-12 and the regulation of innate resistance and adaptive immunity","volume":"3","author":"Trinchieri","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"2025032405421160800_r3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev.iy.13.040195.001343","article-title":"Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity","volume":"13","author":"Trinchieri","year":"1995","journal-title":"Annu. Rev. Immunol."},{"key":"2025032405421160800_r4","doi-asserted-by":"crossref","first-page":"55609","DOI":"10.1074\/jbc.M406565200","article-title":"Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein","volume":"279","author":"Liu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r5","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1084\/jem.20030026","article-title":"Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-\u03b3-primed IL-12 production by IFN regulatory factor 1","volume":"198","author":"Liu","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025032405421160800_r6","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S1074-7613(00)00045-5","article-title":"CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal","volume":"13","author":"Schulz","year":"2000","journal-title":"Immunity"},{"key":"2025032405421160800_r7","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.1128\/MCB.15.10.5258","article-title":"Regulation of interleukin 12 p40 expression through an NF-\u043aB half-site","volume":"15","author":"Murphy","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"2025032405421160800_r8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1084\/jem.183.1.147","article-title":"The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells","volume":"183","author":"Ma","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025032405421160800_r9","doi-asserted-by":"crossref","first-page":"4572","DOI":"10.1128\/MCB.17.8.4572","article-title":"Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C\/EBP and Rel proteins","volume":"17","author":"Plevy","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"2025032405421160800_r10","doi-asserted-by":"crossref","first-page":"5507","DOI":"10.4049\/jimmunol.158.11.5507","article-title":"Accelerated collagen-induced arthritis in IFN-\u03b3 receptor-deficient mice","volume":"158","author":"Vermeire","year":"1997","journal-title":"J. Immunol."},{"key":"2025032405421160800_r11","doi-asserted-by":"crossref","first-page":"4498","DOI":"10.4049\/jimmunol.166.7.4498","article-title":"Suppression of Il-12 transcription in macrophages following Fc\u03b3 receptor ligation","volume":"166","author":"Grazia Cappiello","year":"2001","journal-title":"J. Immunol."},{"key":"2025032405421160800_r12","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1101\/gad.909001","article-title":"NF-\u043aB signaling pathways in mammalian and insect innate immunity","volume":"15","author":"Silverman","year":"2001","journal-title":"Genes Dev."},{"key":"2025032405421160800_r13","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm2083","article-title":"Integrating cell-signalling pathways with NF-\u043aB and IKK function","volume":"8","author":"Perkins","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025032405421160800_r14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1385\/CT:6:2:111","article-title":"The NF-\u043aB regulatory network","volume":"6","author":"Brasier","year":"2006","journal-title":"Cardiovasc. Toxicol."},{"key":"2025032405421160800_r15","doi-asserted-by":"crossref","first-page":"6680","DOI":"10.1038\/sj.onc.1209954","article-title":"Introduction to NF-\u043aB: players, pathways, perspectives","volume":"25","author":"Gilmore","year":"2006","journal-title":"Oncogene"},{"key":"2025032405421160800_r16","doi-asserted-by":"crossref","first-page":"174","DOI":"10.2741\/3920","article-title":"The role of tristetraprolin in cancer and inflammation","volume":"17","author":"Sanduja","year":"2012","journal-title":"Front Biosci (Landmark Ed)"},{"key":"2025032405421160800_r17","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.281.5379.1001","article-title":"Feedback inhibition of macrophage tumor necrosis factor-\u03b1 production by tristetraprolin","volume":"281","author":"Carballo","year":"1998","journal-title":"Science"},{"key":"2025032405421160800_r18","doi-asserted-by":"crossref","first-page":"47958","DOI":"10.1074\/jbc.M109511200","article-title":"HuA and tristetraprolin are induced following T cell activation and display distinct but overlapping RNA binding specificities","volume":"276","author":"Raghavan","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r19","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.1128\/MCB.19.6.4311","article-title":"Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor \u03b1 mRNA","volume":"19","author":"Lai","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"2025032405421160800_r20","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1182\/blood.V95.6.1891","article-title":"Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability","volume":"95","author":"Carballo","year":"2000","journal-title":"Blood"},{"key":"2025032405421160800_r21","doi-asserted-by":"crossref","first-page":"13928","DOI":"10.1074\/jbc.M300016200","article-title":"Tristetraprolin binds to the 3\u2032-untranslated region of cyclooxygenase-2 mRNA. A polyadenylation variant in a cancer cell line lacks the binding site","volume":"278","author":"Sawaoka","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r22","doi-asserted-by":"crossref","first-page":"953","DOI":"10.4049\/jimmunol.174.2.953","article-title":"Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay","volume":"174","author":"Ogilvie","year":"2005","journal-title":"J. Immunol."},{"key":"2025032405421160800_r23","doi-asserted-by":"crossref","first-page":"11689","DOI":"10.1074\/jbc.M709657200","article-title":"Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin","volume":"283","author":"Stoecklin","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r24","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.4049\/jimmunol.180.4.2545","article-title":"Tristetraprolin regulates CXCL1 (KC) mRNA stability","volume":"180","author":"Datta","year":"2008","journal-title":"J. Immunol."},{"key":"2025032405421160800_r25","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1073\/pnas.0400148101","article-title":"Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis","volume":"101","author":"Phillips","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405421160800_r26","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1074-7613(00)80411-2","article-title":"A pathogenetic role for TNF\u03b1 in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency","volume":"4","author":"Taylor","year":"1996","journal-title":"Immunity"},{"key":"2025032405421160800_r27","doi-asserted-by":"crossref","first-page":"29571","DOI":"10.1074\/jbc.M109.031237","article-title":"Tristetraprolin impairs NF-\u043aB\/p65 nuclear translocation","volume":"284","author":"Schichl","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r28","doi-asserted-by":"crossref","first-page":"29383","DOI":"10.1074\/jbc.M109.024745","article-title":"RNA-destabilizing factor tristetraprolin negatively regulates NF-\u043aB signaling","volume":"284","author":"Liang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r29","doi-asserted-by":"crossref","first-page":"40691","DOI":"10.1155\/MI\/2006\/40691","article-title":"Down-regulation of tristetraprolin expression results in enhanced IL-12 and MIP-2 production and reduced MIP-3\u03b1 synthesis in activated macrophages","volume":"2006","author":"Jalonen","year":"2006","journal-title":"Mediators Inflamm."},{"key":"2025032405421160800_r30","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1074\/jbc.M110.154971","article-title":"Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP\/PKA signaling pathway","volume":"286","author":"Qian","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r31","doi-asserted-by":"crossref","first-page":"17827","DOI":"10.1074\/jbc.M001696200","article-title":"Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to AU-rich elements and destabilization of mRNA","volume":"275","author":"Lai","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r32","doi-asserted-by":"crossref","first-page":"6454","DOI":"10.4049\/jimmunol.1002672","article-title":"Posttranscriptional regulation of IL-23 expression by IFN-\u03b3 through tristetraprolin","volume":"186","author":"Qian","year":"2011","journal-title":"J. Immunol."},{"key":"2025032405421160800_r33","doi-asserted-by":"crossref","first-page":"21269","DOI":"10.1074\/jbc.M110.100818","article-title":"Activation of IL-27 p28 gene transcription by interferon regulatory factor 8 in cooperation with interferon regulatory factor 1","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r34","doi-asserted-by":"crossref","first-page":"5150","DOI":"10.4049\/jimmunol.1103700","article-title":"Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype","volume":"188","author":"Qiu","year":"2012","journal-title":"J. Immunol."},{"key":"2025032405421160800_r35","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.4049\/jimmunol.0803883","article-title":"Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10","volume":"183","author":"Schaljo","year":"2009","journal-title":"J. Immunol."},{"key":"2025032405421160800_r36","doi-asserted-by":"crossref","first-page":"13806","DOI":"10.1073\/pnas.95.23.13806","article-title":"Inhibition of interferon gamma induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor","volume":"95","author":"Hodge-Dufour","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405421160800_r37","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.4049\/jimmunol.164.4.1722","article-title":"Inhibition of IL-12 production in human monocyte-derived macrophages by TNF","volume":"164","author":"Ma","year":"2000","journal-title":"J. Immunol."},{"key":"2025032405421160800_r38","doi-asserted-by":"crossref","first-page":"5024","DOI":"10.4049\/jimmunol.175.8.5024","article-title":"Paradoxical anti-inflammatory actions of TNF-\u03b1: inhibition of IL-12 and IL-23 via TNF receptor 1 in macrophages and dendritic cells","volume":"175","author":"Zakharova","year":"2005","journal-title":"J. Immunol."},{"key":"2025032405421160800_r39","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev.immunol.22.012703.104758","article-title":"Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation","volume":"25","author":"Kastelein","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2025032405421160800_r40","doi-asserted-by":"crossref","first-page":"4750","DOI":"10.1128\/IAI.00287-06","article-title":"The circadian clock Period 2 gene regulates \u03b3 interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock","volume":"74","author":"Liu","year":"2006","journal-title":"Infect. Immun."},{"key":"2025032405421160800_r41","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1126\/science.3128869","article-title":"Interferon-\u03b3: the major mediator of resistance against Toxoplasma gondii","volume":"240","author":"Suzuki","year":"1988","journal-title":"Science"},{"key":"2025032405421160800_r42","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/ni1584","article-title":"Post-transcriptional control of cytokine production","volume":"9","author":"Anderson","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025032405421160800_r43","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/nar\/29.1.246","article-title":"ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins","volume":"29","author":"Bakheet","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2025032405421160800_r44","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev.iy.12.040194.001041","article-title":"Function and activation of NF-\u043aB in the immune system","volume":"12","author":"Baeuerle","year":"1994","journal-title":"Annu. Rev. Immunol."},{"key":"2025032405421160800_r45","doi-asserted-by":"crossref","first-page":"19188","DOI":"10.1074\/jbc.M602059200","article-title":"Interferon regulatory factor 8 regulates RANTES gene transcription in cooperation with interferon regulatory factor-1, NF-\u043aB, and PU.1","volume":"281","author":"Liu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2025032405421160800_r46","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1084\/jem.20061440","article-title":"Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-\u03b3-mediated pathways","volume":"204","author":"Liu","year":"2007","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/7\/3922\/62511827\/1300126.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/7\/3922\/62511827\/1300126.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T05:53:09Z","timestamp":1742881989000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/191\/7\/3922\/7989758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,1]]},"references-count":46,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,10,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1300126","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,10]]},"published":{"date-parts":[[2013,10,1]]}}}